Visiting Colloquium Professors - 2012

January 6th 2012

Anthony Grace, Ph.D.

Professor of Neuroscience & Psychology University of Pittsburgh

Dopamine System Dysregulation by the Hippocampus and the Pathophysiology of Schizophrenia

It is generally accepted that a dysfunction of the dopamine system plays a role in the pathophysiology of schizophrenia. However, there is little data to support a pathology within the dopamine system itself; this has given rise to the concept that the dopamine system is being dysregulated by other brain regions. We have shown in rodents that a potent modulator of the dopamine system is the ventral subiculum; a subregion of the hippocampus that is interconnected with limbic brain regions. When examined in the methyl-azoxymethanol (MAM) developmental disruption rodent model of schizophrenia, we found that the ventral subiculum is hyperactive, leading to increased dopamine neuron population activity and behavioral hyper-responsivity to amphetamine. This hyperactivity correlates with a loss of hippocampal parvalbumin interneuron staining and loss of evoked gamma rhythmic activity. Moreover, inactivation of the ventral subiculum restored dopamine neuron firing to control levels and reversed the behavioral hyper-responsivity to amphetamine. These data suggest that, in schizophrenia, a loss of fast-spiking GABAergic parvalbumin interneurons in the hippocampus subiculum leads to an overdrive of dopamine neuron firing, and that this is the pathophysiological basis for the heightened dopamine response in schizophrenia. Antipsychotic drugs can reverse this hyper-responsivity by blocking dopamine receptors downstream from the deficit; however, this approach does not reverse the deficit in the hippocampus, but instead invokes an offsetting deficit in the dopamine system. A more effective treatment would be to restore GABAergic inhibition within the ventral subiculum. We now report that administration of a GABA A alpha-5 selective benzodiazepine, which should selectively potentiate GABAergic processes in the hippocampus, will also reverse the increased dopamine neuron activity and restore the behavioral response to amphetamine to control levels. Therefore, the most effective therapeutic treatment for schizophrenia is not likely to reside in blocking dopamine system function, but instead acting at the site of pathology within the hippocampus.